Glutathione (gamma-L-glutamyl-L-cysteinylglycine) is synthesized by the sequential action of the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase. L-Buthionine-SR-sulfoximine (L-(S-n-butyl)homocysteine-SR-sulfoximine is a potent and specific inhibitor of gamma-glutamylcysteine synthetase. Glutathione synthesis is decreased in tissues and cells treated in vitro or in vivo with the inhibitor and such cells and tissues become glutathione depleted. Tumors in mice treated with the inhibitor become glutathione depleted and more susceptible to the cytotoxic effects of ionizing radiation and various chemotherapeutic agents. (Bump, E.A., et al, International Journal Radiation Oncology, Biology and Physics, Vol. 8, p. 439-442, 1982 and Ozols, R.F., et al, Biochemical Pharmacology, Vol. 36, No. 1, pp. 147-153, 1987). Moreover, mice infected with Trypanosoma b. brucei have been shown to have extended survival and in some cases to be cured by treatment with DL-buthionine-SR-sulfoximine. (Arrick, B.A., et al, J. Exp. Med, Vol. 153, 720-725, March 1981).
A problem encountered in utilizing either DL-buthionine-SR-sulfoximine or L-buthionine-SR-sulfoximine is that very large dosages are often required and such dosages become osmotically burdensome to the treated subject. It has also been reported that L-buthionine-SR-sulfoximine has a deleterious effect on cystine transport (see Brodie, A.E., et al, Toxicology and Applied Pharmacology 77, 381-387, 1985) and on gamma-glutamylamino acid transport (see Anderson, M.E. and Meister, A., Proc. Natl. Acad. Sci., Vol. 80, pp. 707-711, 1983).
Since it has been shown that L-methionine-S-sulfoximine is the only diastereomer of DL-methionine-SR-sulfoximine that inhibits gamma-glutamylcysteine synthetase (Richman, Paul G., et al, The Journal of Biological Chemistry 248, No. 19, 6684-6690, 1973), it has been suspected that L-buthionine-S-sulfoximine is the only diastereomer of DL-buthionine-SR-sulfoximine that inhibits gamma-glutamylcysteine synthetase. If this were true, then the high dosage and osmotic burden associated with the use of the currently available isomer mixtures could be reduced if the pure L-S-isomer were available. Furthermore, the aforementioned deleterious effect on cystine and gamma-glutamylamino acid transport could be reduced if the pure L-S-isomer were available.